Rational design of microRNA-siRNA chimeras for multi-functional target suppression
The present disclosure encompasses methods for rational design of microRNA and small interfering RNA chimeras and compositions and methods of use thereof.
1. A composition, the composition comprising a nucleic acid construct comprising a nucleotide sequence of about 19 to about 25 nucleotides in which nucleotides 2 through 8 are identical to nucleotides 2 through 8 of an miRNA and the rest of the nucleotides are identical to those of a siRNA that specifically hybridizes to a target nucleic acid, wherein nucleotides 2 through 8 are capable of specifically hybridizing to nucleic acids that are naturally regulated by the miRNA and the entire nucleic acid construct is capable of specifically hybridizing to the target nucleic acid targeted by the siRNA.
2. The composition of claim 1 , wherein the siRNA targets AKT1 and the miRNA is miR-200a.
3. The composition of claim 1 , wherein nucleotides 2 through 8 of the siRNA sequence have 1, 2, or 3 mismatches relative to nucleotides 2 through 8 of the construct.
4. The composition of claim 3 , wherein the mismatches are either interspersed or contiguous.
5. The composition of claim 3 , wherein the mismatches are located within nucleotides 5 through 8.
6. The composition of claim 1 , wherein the nucleotide sequence comprises a sequence selected from the group consisting of SEQ ID NO:6, SEQ ID NO:7, SEQ ID NO:8, nucleotides 37-57 of SEQ ID NO:13, and nucleotides 36-56 of SEQ ID NO:15.
7. The composition of claim 1 , wherein the construct is a DNA that codes for the RNA.